8-32648096-G-C

Position:

• chr8-32648096-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001322205.2(NRG1):​c.379G>C​(p.Ala127Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00925 in 1,614,026 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0077 (5 hom., cov: 31)
  • Exomes 𝑓: 0.0094 (90 hom.)
• Consequence: NRG1 NM_001322205.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.35

Genes affected

NRG1 (HGNC:7997): (neuregulin 1) The protein encoded by this gene is a membrane glycoprotein that mediates cell-cell signaling and plays a critical role in the growth and development of multiple organ systems. An extraordinary variety of different isoforms are produced from this gene through alternative promoter usage and splicing. These isoforms are expressed in a tissue-specific manner and differ significantly in their structure, and are classified as types I, II, III, IV, V and VI. Dysregulation of this gene has been linked to diseases such as cancer, schizophrenia, and bipolar disorder (BPD). [provided by RefSeq, Apr 2016]

NRG1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026865602).
• BP6: Variant 8-32648096-G-C is Benign according to our data. Variant chr8-32648096-G-C is described in ClinVar as [Benign]. Clinvar id is 2658528.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0094 (13746/1461884) while in subpopulation MID AF= 0.0284 (164/5768). AF 95% confidence interval is 0.0249. There are 90 homozygotes in gnomad4_exome. There are 6658 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1178 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRG1	NM_013964.5	c.502+31211G>C		intron_variant		ENST00000405005.8	NP_039258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NRG1	ENST00000405005.8	c.502+31211G>C		intron_variant		1	NM_013964.5	ENSP00000384620.2

Frequencies

GnomAD3 genomes AF: 0.00776 AC: 1180 AN: 152024 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00819

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0207

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00956

Gnomad OTH AF: 0.00528

GnomAD3 exomes AF: 0.00920 AC: 2314 AN: 251476 Hom.: 17 AF XY: 0.00934 AC XY: 1270 AN XY: 135914

Gnomad AFR exome AF: 0.00178

Gnomad AMR exome AF: 0.00679

Gnomad ASJ exome AF: 0.0195

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00176

Gnomad FIN exome AF: 0.0229

Gnomad NFE exome AF: 0.0108

Gnomad OTH exome AF: 0.0111

GnomAD4 exome AF: 0.00940 AC: 13746 AN: 1461884 Hom.: 90 Cov.: 35 AF XY: 0.00916 AC XY: 6658 AN XY: 727242

Gnomad4 AFR exome AF: 0.00227

Gnomad4 AMR exome AF: 0.00655

Gnomad4 ASJ exome AF: 0.0188

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00172

Gnomad4 FIN exome AF: 0.0217

Gnomad4 NFE exome AF: 0.00973

Gnomad4 OTH exome AF: 0.00985

GnomAD4 genome AF: 0.00774 AC: 1178 AN: 152142 Hom.: 5 Cov.: 31 AF XY: 0.00807 AC XY: 600 AN XY: 74380

Gnomad4 AFR AF: 0.00181

Gnomad4 AMR AF: 0.00818

Gnomad4 ASJ AF: 0.0228

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0207

Gnomad4 NFE AF: 0.00956

Gnomad4 OTH AF: 0.00523

Alfa AF: 0.00876 Hom.: 7

Bravo AF: 0.00655

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00908 AC: 35

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00930 AC: 80

ExAC AF: 0.00891 AC: 1082

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.00981

EpiControl AF: 0.0108

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2023

NRG1: BP4, BS1, BS2 -

NRG1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 26, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	9.6
DANN	Benign	0.29
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.32	T;.
MetaRNN	Benign	0.0027	T;T
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	2.0	N;N
REVEL	Benign	0.053
Sift	Benign	1.0	T;T
Sift4G	Benign	0.47	T;T
Polyphen		0.0	B;.
Vest4		0.11
MVP		0.068
ClinPred		0.0046	T
GERP RS		4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs34822181; hg19: chr8-32505615;